Ocular graft versus host disease (OGVHD) is a severe ocular surface inflammatory disease (OSID), occurring in patients undergoing allogenic hematopoietic stem cell transplantation (HSCT). OGVHD is characterized by dry eye, meibomian gland dysfunction, conjunctival scarring, lid margin scarring, keratopathy, and corneal ulceration, causing significant ocular morbidity and vision loss for affected patients. Presently, there are no effective disease-modifying therapies for OGVHD. The purpose of this STTR Phase I grant application is to develop novel and effective therapies for the treatment of OGVHD and potentially other OSIDs. The current proposal represents a collaborative effort between Eyedesis Biosciences, a biotechnology company focused on developing calcium / calmodulin-dependent protein kinase kinase 2 (CaMKK2)-targeted therapies for ocular diseases, and scientists at Duke University School of Medicine. Preliminary data demonstrate that (1) OGVHD is associated with infiltration of T cells and macrophages, two types of inflammatory cells in which CaMKK2 has been previously shown to modulate and amplify effector function; (2) the Eyedesis team has developed a proprietary library of small molecule inhibitors of CaMKK2 (SMICs); (3) selected candidate SMICs have been confirmed to inhibit CaMKK2 activity in vitro; (4) the major histocompatibility-mismatch mouse model reproduces clinical findings and pathologic features of OGVHD; (5) local ocular application of the tool compound CaMKK2 inhibitor STO-609 in this OGVHD model reduces severity of OGVHD findings as compared to control-treated mice in preliminary in vivo studies, without signs of apparent drug toxicity. This 12- month Phase I STTR will fund feasibility studies crucial to the development of novel SMICs invented by Eyedesis. During STTR Phase I funding, the study team will work to demonstrate that: (1) novel SMICs are potent inhibitors of T cells and macrophage CaMKK2 and effector function in vitro; (2) these molecules are potent CaMKK2 inhibitors without significant off-target activity; (3) these molecules are well tolerated when applied topically to the eye; and (4) topical administration of SMICs is efficacious in treating OGVHD in a mouse model. The key deliverable will be the identification of at least one candidate SMIC for topical therapy for OGVHD that meets these goals and is suitable for moving forward into formal pre-IND formulation development. Successful realization of the Phase I milestones will justify additional development of SMICs in Phase II, including: (1) clinical formulation for topical administration; and (2) performance of IND-enabling studies (i.e. GLP toxicology and formal pharmacokinetics studies).